The heart is the target organ of several autoimmune responses including those induced by coxsackievirus and group A Streptococcal infections. To examine immune interactions in the heart, we have studied a murine autoimmune myocarditis model induced by autologous cardiac myosin. Two important questions we wished to address with this model are what are the normal mechanisms by which autoimmune responses are prevented, and how are these mechanisms overcome when an autoimmune response does occur? Our previous studies clearly showed that self-reactive T cells are present in normal mice and that the self-antigen is constitutively processed and presented in the heart. Thus, both critical components of a T cell mediated response, T cells and antigen presenting cells displaying the autoantigen in the target organ, are present normally. Studies are proposed which will further characterize this model of myocarditis, with an emphasis regarding the induction process. We will continue our studies on the identification of the myocarditic epitope of mouse cardiac myosin, using synthetic peptides encompassing the entire myosin sequence. A key to these proposed studies is the generation of a transgenic mouse expressing the T cell receptor (TCR) from a T cell specific for autologous cardiac myosin. This TCR-tg mouse will be developed in a B6.AKR inbred mouse strain, which will allow us to transfer T cells from these mice into other B6.AKR mice, without any histoincompatibility problems. Using these TCR-tg T cells, we will ascertain what activation steps of the T cells and/or the host environment are needed for the induction of myocarditis. Additionally, we have identified a fascinating homology between a streptococcal M5 epitope and the Hbb(64-76) determinant, and that tolerance to the Hbb(64-76) determinant affects T cell responses to the M5 epitope. Through the use of Hbb congenic mouse strains, we can directly test our hypothesis that one of the non-MHC polymorphic genes involved in susceptibility to autoimmune diseases is the tolerance to a self-protein. Overall, these studies will increase our understanding of the factors involved in the induction, control, and susceptibility to autoimmune diseases.